The overall goals of this proposal are to comprehensively identify the specific sequence variants involved in the development of idiopathic pulmonary fibrosis (IPF), to explore how these key IPF sequence variants contribute to the etiologic, biologic, and clinical phenotypes of this disease, and then examine the generalizability of these genetic risk variants to other ethnic groups. We chose to focus on IPF in the competitive renewal since IPF is the most common and severe fibrosing idiopathic interstitial pneumonia (fIIP), is a well-defined phenotype (1- 3), is more strongly associated with the MUC5B promoter variant than other forms of fIIP (Table 1) (4, 5), composed 81% of the cases in our GWAS (6), and is associated with 16 of the 24 fIIP GWAS loci (Table 1). The overall concept driving the proposed research is that while our GWAS loci can be used to define risk of disease, identification of the specific variant(s) and gene(s) within the 16 high priority PF loci is needed to make progress on understanding disease pathogenesis (7, 8), prognosis (9-25), treatment (26-29), and survival (30), all of which remain major problems in understanding and treating patients with IPF. The findings from the initial cycle of our R01 lead us to conclude that IPF is caused by rare, uncommon, and common variants in a number of risk genes that function alone and/or in concert with or without cigarette smoking to influence the risk of developing both familial and sporadic forms of IPF and that the genetics of IPF may help us identify disease earlier and understand the biological and clinical heterogeneity of this disease. Based on these findings, we hypothesize that specific gene variants and gene variant x gene variant interactions with or without cigarette smoking result in unique etiologic, biologic, and clinical phenotypes of IPF. In Aim 1, we will sequence these targeted regions (16 loci; 6.17 Mb DNA) in 1500 cases of IPF (200 familial and 1300 sporadic) and 1500 controls; thus identifying a broad range of sequence variants potentially associated with IPF. In Aim 2, we will validate these novel sequence variants in independent populations of patients with sporadic IPF (200 familial and 1300 sporadic) and unaffected controls (N=1500). The goal of Aim 3 is to understand how the specific genetic variants identified in Aims 1 and 2 interact with the MUC5B variant, and then explore MUC5B x gene variant, gene x gene, and gene x smoking interactions, and the relationship of genetic variants and interactions to unique biological and clinical manifestations of IPF. In Aim 4, we plan to examine the generalizability of the genetic risk variants to other ethnic groups.